Millenium Technology Prize 2012: Mouse stem cell research heralds a new era in biomedical research

Every year since 2004 the Technology Academy Finland has awarded the prestigious Millennium Technology Prize as a tribute to life-enhancing technological innovations, and the list of past winners includes some of the world’s leading technological innovators. This year the Grand Prize is for the first time being shared between two innovators, Linus Torvalds, who created the open-source Linux operating system, and Shinya Yamanaka, who created the first induced pluripotent stem (iPS) cells.

The discovery by Professor Shinya Yamanaka of Kyoto University that it was possible to transform adult cells into stem cells that had the ability to then develop into any cell type – an ability only previously observed in embryonic stem cells – by inserting 4 genes associated with embryonic development, has electrified the scientific community, with many groups around the world now working to improve the technique and apply it to medical research and medicine. The Millenium prize notes that Prof. Yamanake first identified the genes required to transform skin cells to pluripotent stem cells through studies in mice.

In 2006 his research team successfully generated mouse induced pluripotent stem cells (iPS) cells with self-renewal and pluripotency (the ability to develop into different types of cell), which are almost equivalent to ES cells. The following year they established human iPS cells, by transducing the same four genes used in their earlier breakthrough, in human adult skin cells.”

The work briefly described above was a technological tour-de-force where Prof. Yamanaka and his colleagues selected 24 genes which had previously been identified as having key roles in mouse embryonic stem cells, and developed a screening method using skin fibroblast cells derived from mice that had be genetically modified with an antibiotic resistance gene that was only expressed in embryonic cells, so that only cells that were in an embryonic state would survive in a culture containing the antibiotic. Different combinations of these 24 genes were screened for their ability to induce to the production of colonies of embryonic -like cells from adult fibroblasts.  They eventually identified just 4 genes – Oct3/, Sox2, Klf4 and c-Myc – that together could reprogram adult mouse fibroblast cells to a pluripotent embryonic-like state (1), and subsequently demonstrated that these iPS cells could give rise to a wide variety of  tissue types when incorporated into mice, either by subcutaneous injection into adult mice or incorporation into early mouse embryos. By modifying their method slightly to also include expression of an important developmental gene named Nanog  they were then able to generate chimeric mice (mice whose tissues are made up of a mixture of cells derived from their own embryonic stem cells, and cells derived from iPS cells) which were capable of transmitting the iPS cells to the next generation of mice (2).

Soon after this Prof. Yamanaka succeeded in generating iPS cells from human fibroblasts, using the same techniques used for the mouse cells, and a whole new and exciting field of biomedical research was born.

Paul Browne

1)      Takahashi K, Yamanaka S. “Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.” Cell 2006 Vol. 126(4):663-76. PubMed: 16904174

2)      Okita K., Ichisaka T., Yamanaka S. “Generation of germline-competent induced pluripotent stem cells.” Nature Vol. 448:313-317 (2007). PubMed:17554338

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